1. Field of the Invention
This invention relates to novel multibinding compounds (agents) that are β2 adrenergic receptor agonists and pharmaceutical compositions comprising such compounds. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of respiratory diseases such as asthma and chronic bronchitis. They are also useful in the treatment of nervous system injury and premature labor.
2. References
The following publications are cited in this application as superscript numbers:                1 Hardman, J. G., et al. “The Pharmacological Basis of Therapeutics”, McGraw-Hill, New York, (1996)        2 Strosberg, A. D. “Structure, Function, and Regulation of Adrenergic Receptors” Protein Sci. 2, 1198-1209 (1993).        3 Beck-Sickinger, A. G. “Structure Characterization and Binding Sites of G-Protein-coupled Receptors” DDT, 1, 502-513, (1996).        4 Hein, L. & Kobilka, B. K. “Adrenergic Receptor Signal Transduction and Regulation” Neuropharmacol, 34, 357-366, (1995).        5 Strosberg, A. D. & Pietri-Rouxel, F. “Function, and Regulation of β3-Adrenoceptor” TiPS, 17, 373-381, (1996).        6 Barnes, P. J. “Current Therapies for Asthma” CHEST, 111:17S-26S (1997).        7 Jack, D. A. “A way of Looking at Agonism and Antagonism:        
Lessons from Salbutamol, Salmeterol and other β-Adrenoceptor Agonists” Br. J. Clin. Pharmac. 31, 501-514, (1991).                8 Kissei Pharmaceutical Co. Ltd. “2-Amino-1-(4-hydroxy-2-methyl-phenyl)propanol derivatives” JP-10152460 (Publication date Jun. 9, 1998).        
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
A receptor is a biological structure with one or more binding domains that reversibly complexes with one or more ligands, where that complexation has biological consequences. Receptors can exist entirely outside the cell (extracellular receptors), within the cell membrane (but presenting sections of the receptor to the extracellular milieu and cytosol), or entirely within the cell (intracellular receptors). They may also function independently of a cell (e.g., clot formation). Receptors within the cell membrane allow a cell to communicate with the space outside of its boundaries (i.e., signaling) as well as to function in the transport of molecules and ions into and out of the cell.
A ligand is a binding partner for a specific receptor or family of receptors. A ligand may be the endogenous ligand for the receptor or alternatively may be a synthetic ligand for the receptor such as a drug, a drug candidate or a pharmacological tool.
The super family of seven transmembrane proteins (7-TMs), also called G-protein coupled receptors (GPCRs), represents one of the most significant classes of membrane bound receptors that communicate changes that occur outside of the cell's boundaries to its interior, triggering a cellular response when appropriate. The G-proteins, when activated, affect a wide range of downstream effector systems both positively and negatively (e.g., ion channels, protein kinase cascades, transcription, transmigration of adhesion proteins and the like).
Adrenergic receptors (AR) are members of the G-prote in coupled receptors that are composed of a family of three receptor sub-types: α1 (A.B.D) α2 (A.B.C), and β (1.2.3).1-5 These receptors are expressed in tissues of various systems and organs of mammals and the proportions of the α and the β receptors are tissue dependant. For example, tissues of bronchial smooth muscle express largely β2-AR while those of cutaneous blood vessels contain exclusively α-AR subtypes.
It has been established that the β2-AR sub-type is involved in respiratory diseases such as such as asthma6, chronic bronchitis, nervous system injury, and premature labor8. Currently, a number of drugs e.g., albuterol, formoterol, isoprenolol, or salmeterol having β2-AR agonist activities are being used to treat asthma. However, these drugs have limited utility as they are either non-selective thereby causing adverse side effects such as muscle tremor, tachycardia, palpitations, and restlesness6, or have short duration of action and/or slow onset time of action.7 Accordingly, there is a need for β2-selective AR agonists that are fast acting and have increased potency and /or longer duration of action.
The multibinding compounds of the present invention fulfill this need.